M. Manning, W. H. Sawyer and coworkers have published a series of papers describing various [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid), 4-valine]-arginine-vasopressin congeners which have anti-vasopressin activity. Among these are Nature, 308 652 (1984), as well as U.S. Pat. Nos. 4,367,225, 4,399,125 and 4,491,577.
All of the Manning compounds have a peptide tail attached at unit 6 of the disulfide ring. The present compounds are distinguished over these by being hexapeptides which have an aromatic basic tail attached to unit 6 and which also have potent vasopressin antagonist activity.
We also have filed earlier U.S. patent applications, Ser. Nos. 673,824 filed Nov. 21, 1984 and 624,542 filed Aug. 28, 1984 which disclose V.sub.1 and V.sub.2 vasopressin antagonists, respectively, whose structures have non-aromatic alkyldiamines at the 7 or 8 position of the vasopressin structure.
None of the art, of which we are aware, discloses vasopressin antagonists which have a bulky, basic group in the tail portion of the VSP structure, such as an amine moiety which has an aromatic ring, and which still retain substantial antagonistic activity.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. In certain structural formulas, the thio members of the Cap and Cys units are added for clarity.
Certain of the peptide art designations used herein are the following: Cap, .beta.-mercapto-.beta.,.beta.-cycloalkylenepropionic acid; Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Mpr, .beta.-mercaptopropionic acid; dPen, .beta.-mercapto, .beta.,.beta.-dimethylpropionic acid or desaminopenicillamine; Tyr(Alk), O-alkyltyrosine; Abu, .alpha.-amino-n-butyric acid; Chg, cyclohexylglycine; Cha, cyclohexylalanine; Pba, .alpha.-aminophenylbutyric acid; Gln, glutamic acid amide or glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Phe(4'-Alk), 4'-alkylphenylalanine; N-MeAla, N-methylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine, Lys, lysine; Arg, arginine; Met, methionine; Asn, asparagine; Sar, sarcosine; Tos, tosylate; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HBT, hydroxybenzotriazole; ACM, acetamidomethyl; Mpa, non-cyclic .beta.-mercaptopropionic acids.
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the oxygen substituent of a tyrosine unit at position 2 or to the 4'-position of a Phe unit at position 3. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Ethyl is preferred. When the term, "vasopressin", is used, it means L-arginine vasopressin (AVP) unless otherwise modified. The 1-(.beta.-mercaptocycloalkylene)-propionic acid unit (Cap) at position 1 is often referred herein as Pmp for convenience since the pentamethylene containing unit is preferred. All the .beta.-mercaptopropionic acids may be, at times, referred to herein as Mpr.